Medical and veterinary diagnosis, therapy and disease prevention often involve the introduction of chemicals to alter the body's function at the molecular level. Advancements in treatment procedures and pharmaceutical development have expanded the scope of available chemical agents. The types of agents that are administered to biological systems include growth factors, gene therapy compositions, chemotherapeutic agents, anti-bacterial agents, a wide variety of natural and synthetic drugs, and the like.
Agent efficacy is a major consideration in the selection of such chemicals. In particular, the practical utility of the agent is significantly impacted by subordinate effects, referred to as side effects, which are produced by an agent in addition to the agent's primary intended function. Such secondary results may be caused by an agent's ability to bind to more than one species of receptor. The exposure of the agent to various receptors produces a range of physiological responses. Side effect may also occur because receptors attach to different types of cells that control various biochemical processes. Consequently, agents that contact multiple receptor sites inside of a biological system may induce an assortment of clinical effects.
Another factor influencing the efficacy of a chemical agent is the agent's ability to produce the intended effect at sites of the body in addition to the target tissue, referred to as decentralized effects. Frequently, it is desirable for the chemical to provide only localized treatment, such as to an injured area or to a surgical site. For example, operations are often accompanied by treatment with heparin to prevent blood clotting at the site of surgery. However, dispersion of heparin to other sites may cause hemorrhaging throughout the body.
Where decentralized effects and side effects caused by an agent are deleterious to the body, the agent's usefulness is limited. Often, the trade-off between benefits and toxicity means a potentially helpful agent can not be employed for therapy due to the undesirable effects that occur as the agent passes through the body. Furthermore, often a less than optimal dosage of agent must be used in order to lessen these undesirable effects. Thus, it is often not possible to conduct treatments with high concentrations of toxic agents and to repeatedly expose the body to drugs for long-term treatments.
The occurrence of undesirable effects is significantly impacted by the agent's route of administration, travel between different parts of the body and excretion from the target site. Routes of administration include intravenous, oral, inhalational, topical, transdermal, subcutaneous, intramuscular, buccal, intra-arterial, intrathecal and rectal. Methods of directly administering are highly beneficial. Such local applications allow a higher bioavailablity of the chemical at the target site. Where the agent must travel extensively through the body to reach the target tissue, the agent may be metabolized in the gut, portal blood or liver prior to entry into other systemic circulation. Moreover, an agent traveling through the circulation to reach its proposed destination may be retained by blood plasma proteins instead of binding to its intended tissue protein. Direct routes are also useful for reducing potential undesirable effects, producing high local concentrations of agent at the treatment site, and continuously attending to chronic conditions.
Special routes of administration are available for dispensing agents directly to a target tissue. The agents may be attached to a carrier that is implanted near the target site, i.e. drug delivery stents. Other local agent delivery devices include microporous balloon catheters, intravascular injection catheters, ultrasound enhanced delivery through microporous balloon catheters, etc. Intra-vascular, intraoperative or intrathecal catheters may also be surgically inserted near the target organ for delivery of agents. In an exemplary case, gene therapy agents are presented to the heart through a catheter that is percutaneously introduced, such as through the femoral artery, and guided upstream into the coronary artery for agent introduction into the perivascular space. Alternatively, the agent is introduced into the left ventricle and epicardium for agent introduction into the pericardial space. In such procedures, access to the pericardium may also be gained intra-vascular or through a thoracotomy.
However, many of the delivery devices mentioned above are not appropriate for prolonged drug delivery, i.e. longer than a few minutes, because they block the flow of blood. Continuous drug delivery over a long period of time may permit increased depth of penetration of the agent into the target site. For example, it is observed that an artery soaked overnight in a dye absorbs the dye through the thickness of the artery to the outer most vessel layer. Where a delivery device must be repeatedly inserted into a treatment site, damage to the vessel walls by the device may occur with each entrance. Furthermore, the repetitive use of traditional stiff porous balloons to deliver fluid has tendency to cause additional damage to the vessel. These porous balloon catheters need a great deal of pressure to stretch the vessel and deliver the drug, often resulting in vessel injury at the contact site. Frequently, shorter treatment times are imposed in attempts to limit damage to the tissue as well as minimize the exposure of other parts of the body to potentially toxic effects. Thus, it is beneficial for delivery devices to permit long-term treatment without repeatedly injuring the body.
It is also advantageous for devices to control the passage of chemicals from the target site to undesirable paths in the body. Where the tissue is exposed to an agent, it is useful to prevent dissemination of the chemical to the other circulatory paths. For example, agents administered to the heart should be prevented from traveling to the systemic circulation. Many of these agents are toxic to the remainder of the body.
Methods of compartmentalizing a chemical within a target site are important for improving an agent's effectiveness and permitting long-term treatment. Many medical procedures are greatly facilitated by techniques for isolating an agent's area of contact. Coronary heart disease, for example, is the most common disease and cause of death in developed nations. In the treatment of atheroslerotic coronary disease, percutaneous transluminal coronary angioplasty (PTCA) may be performed to reduce obstructions in a vessel. PTCA involves the introduction of a catheter with a small dilating balloon at its tip. The catheter is maneuvered through the arteries, often in the arm or leg, to a site in a coronary artery where the vessel has narrowed. The balloon is inflated to increase the cross-sectional area of the vessel.
Although PTCA treatment has a high success rate in widening the vessel, the vessel may re-narrow or re-close afterwards, referred to as “restenosis.” Treatment of restenosis includes delivery of anti-proliferative drugs to the site of the diseased area following PTCA and during the same surgery. Yet, the drug treatment is only mildly effective due to many factors, including the amount of drug that is absorbed by the cells and diffusion of the drug out of the tissue and back into the coronary circulation. Removal of the drug by the blood stream may take place quicker than the time it takes for the onset of restenosis.
In order to address these problems with restenosis treatment and other therapies, it is necessary to administer high concentrations of therapeutic agents over long periods of time. Such intense drug therapy is only possible if the drug is applied exclusively to the target site.
In another example of agent delivery, growth factors, such as basic fibroblast growth factor, are being applied to the heart muscle in the treatment of advanced coronary artery obstructive disease. Growth factor may induce coronary angiogenesis and new coronary collateral blood vessel growth. However, growth factors function indiscriminately to initiate the growth of new vascular structures and may be undesirable to other areas of the body. A problematic aspect of the treatment involves the agent's potential ability to facilitate growth of benign cancerous tumors located outside of the agent's target area. It is essential that the growth factor be applied specifically to the heart and be isolated from other tissues of the body.
In addition, gene therapy agents are widely used for transferring genetic information to certain cells. Gene transfer involves the delivery to target cells of one or more genes along with the sequences for controlling their expression that are embedded within a vector system. Human gene transfer can be done in vivo by viral transduction and physical transfection. It is desirable that the genetic material is maintained at the area of interest for optimal cell targeting.
Some conditions involve many dispersed damaged sites. Indiscrete stenosis, i.e. an obstruction to forward blood flow in the heart, may be represented by numerous lesion sites within several coronary vessels. It is impractical to treat indiscrete stenosis with conventional PCTA because the balloons need to contact each focal lesion and individually open each occluded site. There are risks of vessel damage to insert multiple balloons at many sites. Perfusing the heart with therapeutic drugs may treat indiscrete stenosis. Procedures to perfuse such arteries having multiple occlusions with agent yet isolating agent treatment to the biological mass/organ are of special interest.
During certain cardiovascular procedures, the myocardium is flushed with cardioplegic fluid to temporarily arrest cardiac function. There are devices that are configured to selectively arrest the heart and permit cardiopulmonary by-pass. These devices are aimed at collecting deoxygenated blood before it enters the heart and providing oxygen rich blood to the body without using the heart or lung. Often a venting conduit is included to eliminate all blood from the heart and decompress the chambers. Incoming blood is redirected to an oxygen-providing device, instead of passing through the heart, and then returned to the body. However, these systems are not designed for removal of potentially systemically toxic fluid that is circulating in the coronary arteries.
Still other delivery devices provide for retrograde administering of the agent against the flow of blood through the tissue. Retrograde perfusion in the heart is through the coronary veins, across the capillary beds and to the coronary arteries. A drawback of retrograde profusion is that blood flow must be ceased prior to administering the agent. Moreover, systolic blood flow carries the agent to other parts of the body.
Some systems for fluid delivery and collection have a single catheter and a switch to change between fluid delivery and drainage. One drawback to single catheter devices is that they do not permit simultaneous delivery at one site and collection of those chemicals at another site.
Thus, there is a need for a procedure to isolate the location of agent contact. The system used in such a procedure should allow for prolonged agent treatment to a site while minimizing damage to the tissue. The system should provide for optimal perfusion of a tissue. In particular, a platform for delivering and collecting fluids in the direction of the circulatory flow path of a target site would be advantageous.